From: VERACARE [veracare@rcn.com]
Sent: Monday, August 06, 2001 2:58 PM
To: Bernard A. Schwetz [FDA]; FDA Dockets
Cc: Tommy Thompson [HHS]; Robert Temple [FDA]; Jane Henney [FDA]; Janet Woodcock [FDA]; Dianne Murphy [FDA]; Greg Koski; David LePay [FDA]
Subject: COMMENT ON: Docket #00N-0074 April 24, 2001
Alliance for Human Research Protection (AHRP)
142 West End Ave, Suite 28P
New York, NY 10023
Tel. 212-595-8974 FAX: 212-595-9086
veracare@rcn.com
August 6, 2001
Dr. Bernard Schwetz
Acting Commissioner
Food and Drug Administration
Dockets Management Branch (HFA-305)
Food and Drug Administration
5630 Fishers Lane, Room 1061
Rockville, MD 20857
Re: COMMENT ON: Docket #00N-0074 April 24, 2001 Interim Rule: "Additional
Safeguards for Children in Clinical Investigations of FDA-Regulated Products
Dear Dr. Schwetz:
Thank you for the opportunity to comment on the interim rule published in the
Federal Register on April 24, 2001 concerning 21 CFR Parts 50 and 56.
We SUPPORT FDA’s decision to adopt HHS 45 CFR 46 Subpart D, EXCLUDING Section
46.408(c), pursuant to bringing FDA regulations into compliance with
provisions of the Children’s Health Act of 2000, which requires that all
research involving children conducted, supported, or regulated by HHS be in
compliance with HHS regulations to provide additional protections for
children involved as research subjects. The rule applies to FDA’s authority
to regulate safety and effectiveness testing in children of such products as:
human drugs and biologicals, medical devices, and dietary supplements,
nutritionals, food additives, and foods.
45 CFR Subpart D, 46.408 (c) states: "If the IRB determines that a research
protocol is designed for conditions or for a subject population for which
parental or guardian permission is not a reasonable requirement to protect
the subjects (for example, neglected or abused children), it may waive the
consent requirements in Subpart A of this part …provided an appropriate
mechanism for protecting the children who will participate as subjects in the
research is substituted, and provided further that the waiver is not
inconsistent with Federal, State, or local law. The choice of an appropriate
mechanism would depend upon the nature and purpose of the activities
described in the protocol, the risk and anticipated benefit to the research
subjects, and their age, maturity, status, and condition."
This language departs significantly from basic tenets of law and
ethics--without any justifiable criteria specified. The issue of surrogacy,
i.e., the appointment of a third party to represent the child's interests,
[make bold i]s not relevant until and unless parental rights have been
terminated. Thus, surrogacy should not be an option for researchers seeking
human subjects.
Clearly, there is no justification for waiving parental permission under any
other circumstances. It is also clear that such rights are not waived even
when the child has been deemed dependent and has been placed in state care as
a ward.
The FDA RIGHTLY chose NOT TO PERMIT the section 46.408 (c) waiver by IRBs of
parental or guardian permission, as it leaves the specific circumstances for
such a violation of parental rights to the discretion of local Institutional
Review Boards (IRB).
Given the torrent of revelations of gross ethical and
procedural violations at one after another of the nation's premier research
institutions, assumptions that "procedural safeguards are in place," or that
IRBs can be relied upon to make decisions that protect the best interests of
human subjects--adults and children--has been debunked.
Sadly, there is no established "appropriate
mechanism," no procedural safeguards, and no system of IRB accountability
on which we can rely.
Children are being experimented upon without regard for their safety or the
pain and suffering inflicted on them. For example, the Boston Globe reported
that experimental eye surgeries being conducted at the University of South
Florida had caused "more than the usual complications, including transplants
that slipped and wounds that broke open." A toddler was subjected to "a
self-contained experiment" in which traditional surgery was performed on one
eye, and a new technique on the other, resulting in "unusual bleeding into
the eye." Children are unjustifiably exposed to pain and suffering for
research.
To recruit ever greater numbers of children for experiments involving risks
of harm ( some of which may prove to be long-term harm ) without any demonstrable "appropriate mechanisms" in place, is reckless endangerment, not
"added protection."
Thus, we urge FDA to reconsider its recent adoption of a broad interpretation
of the meaning of regulatory language related to recruitment qualifications.
Previously, the enrollment of children was restricted to studies that offered
a potential benefit for a specific, identifiable medical condition. FDA
redefined the terms "potential benefit" and "condition" in April 2000 to mean
an unspecified risk or disposition to a common (even minor) condition: "any
child has the potential to benefit from a treatment for otitis media" (ear
infection).
The FDA RIGHTLY concluded that section 46.408(c) is NOT permitted under FDA
law. Thus, pursuant to the requirements of the Federal Administrative
Procedures Act, adoption by the FDA of the section 46.408(c) IRB waiver
authority would require an act of Congress.
We further urge that the FDA resist any pressure to change its legislative
authority in this regard for the following reasons:
1. Parental and guardian rights to grant or withhold permission
should not be waived except under the extraordinary circumstances wherein the
courts adjudicate the existence of abuse or neglect and terminate parental
rights. Permitting IRBs to exercise the Section 46.408(c) waiver authority is
tantamount to abrogating the entire system of judicial protection of children
whose life safety or morals are put into jeopardy. There is a very heavy
burden of proof on those would argue for removal of the traditional court
jurisdiction just because the child is desired as a research subject by some
interested biomedical researcher to show how his/her prudential standard is
at least as high as that of a proper court of jurisdiction.
Indeed, the only proper way to test the equivalence of IRB and court
prudential standards would be for the interested biomedical researcher and
supportive IRB to petition the appropriate court of jurisdiction to grant its
request to waiver parental or guardian consent in the specific research
circumstances. If the FDA were to adopt regulations that permitted IRBs to
exercise the section 46.408(c) waiver authority, one could anticipate a swift
and immediate test of its decision under the Federal Administrative
Procedures Act and, that failing, an appeal to an appropriate federal
district court of jurisdiction. One can also anticipate very messy news media
and political reverberations if children and adolescents were to be recruited
into medical experiments without parental permission.
2.Those who argue that IRBs are capable of developing a mechanism of review
to assure that the child or adolescent is capable of making the decision to
participate in specific research and to provide appropriate procedural
safeguards to protect his/her welfare in the research process are deluding
themselves in so far as the system is unraveling in public view. A steady
stream of investigative reports and research shut downs has revealed that the
IRB system as constituted under existing law and regulations is demonstrably
dysfunctional and fundamentally flawed--even the nation’s most prestigious
biomedical research institutions have been found to be violating basic safeguards.
Gross violation of ethical standards and regulatory procedures that ensure the safety of people in
research are not the exception, they are the sad everyday reality.
3. Those who are promoting the adoption of 46.408 (c) to lift safeguards such
as the involvement of parents in the protection of their children are in fact
arguing to weaken safeguards for children, not to improve them. Informed
consent for adults can be waived for adult subjects only if "the research
involves no more than minimal risk to the subjects" 45 CFR 46.116.
(d).
We note with profound concern that the language of HHS Subpart D, section
46.408 (c) blithely dismisses this restriction with the unfounded assurance
that:
"The choice of an appropriate mechanism would depend upon the nature and
purpose of the activities described in the protocol, the risk and anticipated
benefit to the research subjects, and their age, maturity, status, and
condition."
The clear implication of this deviation from the standards for adult research
protections is that dependent children and adolescents merit even less
protection and concern than do adults.
4. We SUPPORT FDA's retention of the terms "permission,"
"guardian" and "informed consent" -- so as to distinguish children from other
participants in clinical investigations who can exercise the right to
informed consent. Children are defined as "persons who have not attained the
legal age for consent to treatments or procedures involved in clinical
investigations." Thus, by definition, children cannot give informed consent.
"Because children are unable, due to age, to give consent themselves,
permission is provided by a parent or guardian on their behalf. The term
informed consent under Section 50.20 applies to other participants in
clinical investigations."
5. Those who argue that Section 46.408(c) waiver authority is needed to
permit biomedical and behavioral researchers to enroll children and
adolescents with a propensity for risky behaviors involving sexually
transmitted diseases, for experimental research projects, carry a very heavy
burden of proof. They must demonstrate that the research they envision does
not put children at undue risk of harm and that the research offers benefits to the children and
adolescents that outweigh the basic right and duty of parents and guardians
to intervene to protect them from these illnesses and risky behaviors--as
well as to choose appropriate medical interventions. It would be a
gross dereliction of duty for government agencies to permit
IRBs to exercise the Section 46.408(c) waiver of parental authority. Such a policy undercuts
the responsibility of parents and guardians to safeguard the welfare and
morals of children and adolescents and appears to have been
designed solely in order to facilitate their recruitment for research purposes.
Most responsible parents will recoil at the suggestion that biomedical
researchers and their supporting Institutional Review Boards are more able
than the parents or guardians to decide what is in the child's best interests. What is more, the courts with jurisdiction to intervene to protect children from abuse and neglect at the hands of parents or guardians will surely take a dim view of such a claim by
government-- especially in view of widespread evidence of unethical conduct
by researchers in the nation’s most prestigious biomedical research
institutions.
6. We DISAGREE with the unpredictability of current criteria for the
assessment of risks and the inconsistencies that have been shown to arise as
a result. The National Bioethics Advisory Commission (NBAC) recommendations,
if endorsed and adopted, would improve research safeguards for adults and
children. First, we concur with NBAC's analysis [ch 3, p. 25] about the
inherent flaw in current regulations that has encouraged IRBs to designate
risks into categories such as "minimal risk"-- without first examining both
the probability and degree of severity of risks. This lack of clarity has
fostered misrepresentation about the nature of the risks involved to
prospective subjects. IRBs are thereby undermining the prospective research
participant's ability to both evaluate and minimize all aspects of the risks
involved.
The NBAC recommended framework for analyzing risks is on a two-dimensional
continuum: (a) the probability (likelihood) of harm, from zero to certainty
of harm, and (b) the magnitude (severity) of potential harm, from trivial to
fatal. This approach is scientifically sound and facilitates improvement of safeguards for human subjects, including children. It also leads to standardized full disclosure of risks to patients with the
eventual creation of a database for use by future researchers.
We STRONGLY DISAGREE with FDA's deference to IRB discretion regarding the approval process for "Clinical Investigations Involving Greater than Minimal Risk and No Prospect of Direct
Benefit to Individual Subjects, But Likely to Yield Generalizable Knowledge
About the Subjects' Disorder or Condition." That process has been shown to
have resulted in preventable harm--including deaths--even in experiments
deemed potentially beneficial.
Indeed, the evidence of high-risk experiments that have harmed children
demonstrates their vulnerability and need of protection from exploitation.
The following unethical experiments have been tracked by the Alliance for Human Research Protection (AHRP):
* 100 children and babies with gastroesophageal reflux were subjected to a
fatal Propulsid drug trial after the drug was linked to deaths;
* 68 children with hypertrophic cardiomyopathy were subjected to a NIH
pacemaker experiment under coercion, some died others' condition worsened;
Preschool children are being recruited into an NIMH sponsored psychotropic
drug trial that offers parents $645 above expenses if the children--some not
even toilet trained-- complete the 45 week experiment to test the effects of
methylphenidate;
* Soon after Eli Lilly's powerful antipsychotic drug, olanzapine (Zyprexa) was
approved for adult schizophrenia patients, 6 to 11 year old children were
recruited for a clinical trial--despite the drug's documented serious adverse
effects. ALL children experienced adverse effects, such as sedation, weight
gain up to 16 pounds, extreme restlessness (akathesia)--none of the children
were helped. The study was terminated before 6 weeks.
* 100 inner city minority children, aged 6 to 11, were exposed to a toxic drug
Fenfluramine, that was subsequently withdrawn from the market. Thirty-four of the children were not diagnosed with ANY medical condition; the experiment was conducted to
prove the children's predisposition to violence on the researchers' unfounded and inflammatory assumption that siblings of incarcerated brothers are "at risk" of a non-defined, non-medical condition, i.e., future violence.
* 45 children (6 to 12 years old) were subjected to methylphenidate /
dextroamphetamine / pemoline and the pain and risks of spinal taps for
non-therapeutic research purposes.
We STRONGLY DISAGREE with FDA's willingness to waive public review of the
Commissioner's decision in cases in which a high risk clinical investigation
may proceed "that is not otherwise approvable but presents an opportunity to
understand, prevent or alleviate a serious problem affecting the health and
welfare of children." Section 50.54(b) (consistent with 45 CFR 46.407)
requires that "The Commissioner is to consult with a panel of
experts…following public review and comment on the Commissioner's pending
decision." FDA's April 24, 2001 statement in the Federal Register [FR, 20594]
indicates that public review may be denied if "the sponsor is unwilling to
publicly disclose necessary information" is legally, ethically and
politically untenable. FDA is putting corporate interests ahead of child protection. Only national security considerations would warrant the proposed cloak of secrecy for unwilling
sponsors.
The NBAC recommendation proposes that research studies "with risks falling on
the extreme upper end of the continuum--very risky or unknown risks--" should
not be left to the discretion of one local IRB, but rather should be reviewed
by "a national review panel, with public input into the review process."
[Ch.3, p 25, L 19] NBAC's recommendation serves the public
interest and should be adopted.
Attached is our letter of dissent with NHRPAC's draft recommendation, which
provides greater detail about child welfare law.
Thank you very much for your consideration. We would be happy to meet with
FDA staff to discuss these matters in greater depth.
Sincerely,
Vera Hassner Sharav
John H. Noble, Jr., Ph.D
Howard Fishman, MEd, MSW
Alliance for Human Research Protection (AHRP)
cc: David Lepay, M.D. FDA
Greg Koski, PhD, M.D. OHRP
Dianne Murphy, M.D., FDA
Janet Woodcock, M.D., FDA
Robert Temple, M.D., FDA
Duane Alexander, M.D. NICHD
Stephen Hyman, M.D. NIMH
Marcia J. Van Note IG
Michael F. Mangano IG
D. McCarty Thornton IG
Tommy Thompson
Jay Katz, M.D.
Marcia Angell, M.D., FACP
Brennan Troyen, M.D.
Eleanor Shore, M.D., MPH
Carl Elliott, M.D., Ph.D
Thomas Bodenheimer, M.D.
Robert Jay Lifton, M.D., Ph.D
Alan Lichtin, M.D.
Allan Dershowitz, Esq
Lawrence Altman, M.D
William Hirschhorn, M.D..
George Annas, JD, MPH
Elliot Valenstein, Ph.D
Daniel Vasgird, Ph.D
Steve Hanlon, Esq
Denise Nagle, M.D.
Jeffrey Cooper, M.D.
Alan Swann, M.D.
William Carey, M.D.
Harold Vanderpool, M.D.
Robert Saxer, M.D.
Kenneth Rothman, Ph.D
Dan Cresen, M.D.
Richard Epstien, M.D.
Alexander Capron, LL.B
Dale Hammerschmidt, MD
Jay Cohen, M.D.
Loren Mosher, M.D.
Alan Milstein, Esq
Charles Weijer, M.D., Ph.D
Jeffrey Cooper, M.D.
Leonard Glantz, Ph.D
John Janofsky, Esq
Anthony D'Amico, Esq
Bart Campbell, M.D.
Elizabeth Loftus, PhD
Nathaniel Lehrman, M.D.
David Cohen, Ph.D
Scott Gottlieb, M.D.
Andy Vickery, Esq
Glenn McGee, Ph.D.
Ivan Oransky, M.D.
Carl Nugent, M.D.
Lawrence Diller, M.D.
Chris Barden, Esq.
David Egilman, M.D.
John Brown, PhD
Donald Light, Ph.D
Howard Garb PhD
Richard McNally, PhD
Peter Lurie, MD, PC
Marion Wright Edelman, Children's Defense Fund
Heritage Foundation
Alta Charo, J.D.
Charles Siegel, Esq
Martha Churchill, Esq
Simcha Plisner, JD
Paula Werme, Esq
STOP PATIENT ABUSE NOW (SPAN)
Sen. John McCain
Sen. Edward Kennedy
Sen. Bill Frist
Sen. Orin Hatch
Sen. Richard Lugar
Sen. Christopher Dodd
Sen. Susan Collins
Sen. Joseph Lieberman
Sen. Jeff Sessions
Sen. Paul Wellstone
Sen. Judd Gregg
Sen. Mike Enzi
Sen. Charles Schumer
Cong Henry Waxman
Cong. Dianna DeGette
Cong Kucinich
Cong Jim Greenwood
Cong. George Nethercutt
Cong. Dave Weldon
Cong John LaFalce
Cong. Constance Morella
Cong John Peterson
Cong Steve LaTourette
Cong Ed Whitefield
Cong Jerrold Nadler
____________________
Footnotes:
It is important to note that such legal and ethical niceties are frequently
ignored by spokespersons for the child abuse industry. The risks attendant to
being in State care will be discussed elsewhere in this statement, but are
raised here to underscore the fact that a great deal of research is currently
ongoing with this population that is both illegal and unethical.
"I did not expect, or want, to complete my tenure as secretary of health and
human services by raising questions about the safety of patients in clinical
research. However, recent developments leave me little choice." Shalala D,
"Protecting Research Subjects--What Must Be Done," NEJM, Sept. 14, 2000, vol
343:
Dembner A, "Who's protecting the children?" The Boston Globe, March 25, 2001,
front page
Children are being recruited aggressively to be test subjects in psychotropic
drug trials that were approved for conditions the children do not have. In
the process they are suffering severe adverse effects in trials intended to
expand the pediatric market, not to benefit them. Sharav VH, "Evidence
Demonstrating the Need for A National Human Subject Protection Act," 2001,
under publication review.
FDA adopted on April 19, 2000 the recommendation of its "Ethics Working Group
Consensus Statement on the Pediatric Advisory Subcommittee’s November 15,
1999 Meeting. http://www.fda.gov/cder/pediatric/ethics-statement.htm
Since 1998, Federal investigations have made clear that non-compliance with
ethical standards and Federal regulations was widespread. Research at six
institutions was shutdown: *Rush-Presbyterian-St. Luke's Medical Center;
*Friends Research Institute, Inc., West Coast Division; *Veterans Affairs
Greater Los Angeles Health Care System; *Duke University Medical Center;
*Virginia Commonwealth University; *University of Oklahoma, Tulsa Campus [See
OHRP website, letters of determination].
At three other institutions, all federally funded research was suspended:
*University of Illinois, Chicago; *University of Alabama, Birmingham;
*University of Texas Medical Branch at Galveston. [see OHRP website, letters
of determination] From January 1, 1999, to June 2000, approximately 60
institutions, including some of our most prestigious universities, were found
non-compliant.
Since July 2000, OHRP has suspended Federally funded clinical trials at seven
additional research centers: University of Texas Medical Branch at Galveston
(July 10, 2000 letter); *University of Miami (July 31, 2000 letter);
*Northeast Georgia Medical Center (August 4, 200 letter; *Brook Army Medical
Center (October 3, 2000 letter); *National Institute of Health (November 3,
2000); suspension of a single NICHD intramural research project involving
children); *University of Texas Southwestern Medical Center (January 23,
2001); *Florida Department of Health (February 16, 2001 letter). And on July
19, 2001 all federally funded research was suspended at Johns Hopkins
University.